Creutzfeldt-Jakob disease: one hundred years of participation in the design of the transmissible spongiform encephalopathies / Doença de Creutzfeldt-Jakob: cem anos de participação no desenho das encefalopatias espongiformes transmissíveis

Creutzfeldt and Jakob's disease (CJD) has its initial milestone in the publication issued 100 years ago that precipitated its better clinical-pathological and etiological understanding. Now, it is established that it belongs to the group of the prion diseases or transmissible spongiform encephalopathies family. CJD is itself divided into several types, the most common being sporadic that is further subdivided according to the anatomoclinical expression, but mainly due to its aetiology regarding prionic protein or genotype.

A doença de Creutzfeldt e Jakob (CJD) tem seu marco inicial na publicação emitida há 100 anos que precipitou seu melhor entendimento clínico- patológico e etiológico. Agora, está estabelecido que pertence ao grupo da família das doenças de príons ou encefalopatias espongiformes transmissíveis. A própria CJD se divide em vários tipos, sendo o mais comum o esporádico que também se subdivide de acordo com a expressão anatomoclínica, mas principalmente devido à sua etiologia em relação à proteína priônica ou genótipo.

Identification of single nucleotide polymorphisms in the prion protein gene in Santa Ines and Dorset sheep / Identificação de polimorfismos de nucleotídeos únicos em ovinos Santa Inês e Dorset através do gene da proteína priônica

Scrapie is a transmissible spongiform encephalopathy (TSE) that affects sheep and goats and results from accumulation of the abnormal isoform of a prion protein in the central nervous system. Resistance or susceptibility to the disease is dependent on several factors, including the strain of infecting agent, the degree of exposure, and the presence of single nucleotide polymorphisms (SNPs) in the prion protein gene. The most important polymorphisms are present in codons 136, 154, and 171. SNPs have also been identified in other codons, such as 118, 127, 141, 142, and 143. The objective of this study was to investigate the genotypic profile of Santa Ines (n=94) and Dorset (n=69) sheep and identify polymorphisms in the prion protein gene using real-time PCR techniques and sequencing. We analyzed SNPs in 10 different codons (127, 136, 138, 140, 141, 142, 143, 154, 171, and 172) in Santa Ines sheep. Classification of the flock into risk groups associated with scrapie revealed that approximately 68% of the Santa Ines herd was considered at moderate risk (group 3), and the most frequent haplotype was ARQ/ARQ (47.8%). For Dorset sheep, 42% of the herd was considered at moderate risk (group 3), 40% at low risk (group 2), and 12% at very low risk (group 1). These findings improve our understanding of the genotype breed and further highlight the importance of genotyping and identification of polymorphisms in Brazilian herds to assess their effects on potential infections upon exposure to the sheep prion.(AU)

Scrapie é uma encefalopatia espongiforme transmissível que afeta ovinos e caprinos, resultante do acúmulo de uma isoforma anormal da proteína priônica no sistema nervoso central. A resistência ou susceptibilidade está relacionada a diversos fatores, tais como, a cepa do agente infectante, o grau de exposição e o polimorfismo de nucleotídeo único (SNPs) do gene da proteína priônica. Os principais polimorfismos estão presentes nos códons 136, 154 e 171. SNPs também são identificadas em outros códons, tais como, 118, 127, 141, 142, e 143. O objetivo do trabalho foi descrever o perfil genotípico de um rebanho da raça Santa Inês (n=94) e um rebanho da raça Dorset (n=89) para identificar potenciais polimorfismos através da técnica de PCR em tempo real e sequenciamento. Os achados no rebanho Santa Inês indicaram a presença de polimorfismos de nucleotídeos únicos em 10 códons diferentes (127, 136, 138, 140, 141, 142, 143, 154, 171 e 172). A classificação do rebanho, quanto aos grupos de risco associados ao scrapie, relevaram que aproximadamente 68% dos ovinos foram considerados do grupo de risco moderado (grupo 3), onde o haplótipo mais frequente foi ARQ/ARQ (47,8%). Para os ovinos da raça Dorset, 42% do rebanho foi considerado do grupo de risco moderado (grupo 3), 40% do grupo de risco baixo (grupo 2) e 12% do grupo de risco muito baixo. Os dados encontrados contribuem para o conhecimento do genótipo das raças, destacando a importância de trabalhos que relatam os polimorfismos genéticos para a identificação de rebanhos brasileiros, bem como o seu impacto a infecções com exposição ao príon ovino.(AU)

[Psychiatric manifestations by prions. A narrative review]. / Manifestaciones psiquiátricas por priones. Una revisión narrativa.

Prion diseases are a group of rare and rapidly progressive neurodegenerative conditions that may cause neuropsychiatric symptoms. This group of diseases has been described since the 18(th) century, but they were recognized decades later, when it became clear that the humans were affected by infected animals. There was controversy when the problem was attributed to a single protein with infective capacity. The common pathological process is characterized by the conversion of the normal cellular prion protein into an abnormal form. In humans, the illness has been classified as idiopathic, inherited and acquired through exposure to exogenous material containing abnormal prions. The most prominent neurological manifestation of prion diseases is the emergence of a rapidly progressive dementia, mioclonus associated with cerebellar ataxia and also extra pyramidal symptoms. Psychiatric symptoms occur in early stages of the illness and can contribute to timely diagnosis of this syndrome. Psychiatric symptoms have traditionally been grouped in three categories: affective symptoms, impaired motor function and psychotic symptoms. Such events usually occur during the prodromal period prior to the neurological manifestations and consists in the presence of social isolation, onset of delusions, irritability/aggression, visual hallucinations, anxiety and depression, and less frequent first-rank symptoms among others. Definite diagnosis requires post mortem examination. The possibility that a large number of cases may occur in the next years or that many cases have not been considered with this diagnosis is a fact. In our opinion, psychiatrists should be aware of symptoms of this disease. The main objective of this research consisted of assessing the correlation between this disturbance and neuro-psychiatric symptoms and particularly if this psychiatric manifestations integrate a clinical picture suggestive for the diagnosis of these diseases, but firstly reviewed taxonomic, pathogenic and pathological aspects. The authors of this project also added an element in relation to some diagnostic considerations based on scientific evidence. For the search controlled descriptors applied to the research for indexing scientific articles in databases were used. The electronic data bases used were PubMed, EMBASE and also PsycInfo. The descriptors were prion diseases, psychotic disorders, depression, mood disorders, pathology, classification, prion protein, history, neurological manifestations, and psychiatric manifestations. The selection criteria for the material were qualitative. To conclude, and based on the extensive literature review, the authors propose that the period where the evidence is more robust for mental impaired is named "psychiatric symptoms phase, which can be extended for a few months, being the psychiatric affective symptoms the most characteristic of this phase. In conclusion, we considered that the identification of these symptoms in a patient with risk factors for developing the disease will contribute to the early identification, and would regulate the guidelines in suspected diagnosis of this group of disorders. The intention is provide a better quality of life to the sick people.

Manifestaciones psiquiátricas por priones. Una revisión narrativa / Psychiatric manifestations by prions. A narrative review

Las enfermedades priónicas son un grupo de enfermedades neurodegenerativas raras y rápidamente progresivas que causan síntomas neuropsiquiátricos diversos. Estas enfermedades se describieron hace más de 200 arios, y con el tiempo se reconoció que los animales eran portadores de esta alteración; sin embargo, hasta finales de los noventa este problema conmocionó Europa, ya que para entonces la enfermedad había cruzado la barrera de especie y podía afectar al hombre. La polémica fue mayor al atribuirse la alteración a una proteína con capacidad infecciosa. El proceso patológico común se caracteriza por la conversión de la proteína priónica celular normal (PsPc) a una forma anómala y patológica (PrPSc). En el ser humano se han clasificado como padecimientos idiopáticos, hereditarios o adquiridos por la exposición a material exógeno con contenido priónico. La manifestación neurológica más sobresaliente de las prionopatías consiste en la aparición de una demencia rápidamente progresiva asociada a mioclonías y ataxia cerebelosa, además de síntomas extrapiramidales. Los síntomas psiquiátricos ocurren en etapas tempranas de la enfermedad y su presencia, además de la valoración de factores de riesgo, puede contribuir al diagnóstico oportuno de este síndrome. Clásicamente los síntomas psiquiátricos se han agrupado en tres categorías: síntomas afectivos, alteraciones de la motricidad y síntomas psicóticos. Este tipo de manifestaciones suele aparecer durante un periodo prodrómico previo a los signos neurológicos y consiste en la aparición de aislamiento social, ideas delirantes, irritabilidad/agresión, alucinaciones predominantemente visuales, ansiedad y depresión, así como otros menos frecuentes. El diagnóstico definitivo requiere de un estudio post mortem. La posibilidad de que un número mayor de casos pueda ocurrir en los próximos años o que en muchos pacientes no se haya considerado el diagnóstico es una realidad. En opinión de los autores de este trabajo, los psiquiatras debemos tener conocimiento de los síntomas de esta enfermedad. El objetivo de esta investigación es evaluar las alteraciones neuropsiquiátricas presentes en las prionopatías y, en particular, determinar si las manifestaciones psiquiátricas en conjunto integran un cuadro clínico que apunte al diagnóstico de estas enfermedades, aunque en primer término se revisan aspectos taxonómicos, patogénicos y patológicos. Como elemento agregado en este trabajo, los autores hacen algunas consideraciones diagnósticas basadas en la evidencia científica disponible hasta el momento. Los descriptores controlados aplicados a la búsqueda bibliográfica son los utilizados para indexación de artículos científicos en las bases de datos. Las bases de datos y EMBASE, aunque también se empleó PsycInfo. Los descriptores empleados son: enfermedades priónicas, trastornos psicóticos, depresión, trastornos afectivos, patología, clasificación, proteína priónica, historia, manifestaciones neurológicas y manifestaciones psiquiátricas. Los criterios de selección de material fueron cualitativos. Como conclusión y con base en la extensa bibliografía revisada, los autores plantean que el periodo en que hay más evidencia de alteraciones en la esfera mental se denomine «fase de síntomas psiquiátricos¼, la cual puede extenderse por algunos meses (hasta 4). Los síntomas afectivos son los más característicos de dicha fase. Como conclusiones, se considera que la identificación de estos síntomas en un paciente con factores de riesgo de sufrir esta enfermedad contribuiría a la identificación temprana del padecimiento y normaría qué pautas seguir ante la sospecha del diagnóstico de este grupo de trastornos, sobre todo con la idea de mejorar la calidad de vida de estos pacientes.

Prion diseases are a group of rare and rapidly progressive neurodegenerative conditions that may cause neuropsychiatric symptoms. This group of diseases has been described since the 18th century, but they were recognized decades later, when it became clear that the humans were affected by infected animals. There was controversy when the problem was attributed to a single protein with infective capacity. The common pathological process is characterized by the conversion of the normal cellular prion protein into an abnormal form. In humans, the illness has been classified as idiopathic, inherited and acquired through exposure to exogenous material containing abnormal prions. The most prominent neurological manifestation of prion diseases is the emergence of a rapidly progressive dementia, mioclonus associated with cerebellar ataxia and also extra pyramidal symptoms. Psychiatric symptoms occur in early stages of the illness and can contribute to timely diagnosis of this syndrome. Psychiatric symptoms have traditionally been grouped in three categories: affective symptoms, impaired motor function and psychotic symptoms. Such events usually occur during the prodromal period prior to the neurological manifestations and consists in the presence of social isolation, onset of delusions, irritability/aggression, visual hallucinations, anxiety and depression, and less frequent first-rank symptoms among others. Definite diagnosis requires post mortem examination. The possibility that a large number of cases may occur in the next years or that many cases have not been considered with this diagnosis is a fact. In our opinion, psychiatrists should be aware of symptoms of this disease. The main objective of this research consisted of assessing the correlation between this disturbance and neuro-psychiatric symptoms and particularly if this psychiatric manifestations integrate a clinical picture suggestive for the diagnosis of these diseases, but firstly reviewed taxonomic, pathogenic and pathological aspects. The authors of this project also added an element in relation to some diagnostic considerations based on scientific evidence. For the search controlled descriptors applied to the research for indexing scientific articles in databases were used. The electronic data bases used were PubMed, EMBASE and also PsycInfo. The descriptors were prion diseases, psychotic disorders, depression, mood disorders, pathology, classification, prion protein, history, neurological manifestations, and psychiatric manifestations. The selection criteria for the material were qualitative. To conclude, and based on the extensive literature review, the authors propose that the period where the evidence is more robust for mental impaired is named "psychiatric symptoms phase, which can be extended for a few months, being the psychiatric affective symptoms the most characteristic of this phase. In conclusion, we considered that the identification of these symptoms in a patient with risk factors for developing the disease will contribute to the early identification, and would regulate the guidelines in suspected diagnosis of this group of disorders. The intention is provide a better quality of life to the sick people.

Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease / Polimorfismo do codon 129 do gene da proteina prionica nao e fator de risco para doenca de Alzheimer

Interaction of prion protein and amyloid-b oligomers has been demonstrated recently. Homozygosity at prion protein gene (PRNP) codon 129 is associated with higher risk for Creutzfeldt-Jakob disease. This polymorphism has been addressed as a possible risk factor in Alzheimer disease (AD). Objective To describe the association between codon 129 polymorphisms and AD. Methods We investigated the association of codon 129 polymorphism of PRNP in 99 AD patients and 111 controls, and the association between this polymorphism and cognitive performance. Other polymorphisms of PRNP and additive effect of apolipoprotein E gene (ApoE) were evaluated. Results Codon 129 genotype distribution in AD 45.5% methionine (MM), 42.2% methionine valine (MV), 12.1% valine (VV); and 39.6% MM, 50.5% MV, 9.9% VV among controls (p>0.05). There were no differences of cognitive performance concerning codon 129. Stratification according to ApoE genotype did not reveal difference between groups. Conclusion Codon 129 polymorphism is not a risk factor for AD in Brazilian patients.

Polimorfismo do códon 129 do gene da proteína priônica não é fator de risco para doença de Alzheimer A interação entre proteína priônica e oligômeros b-amiloide foi demonstrada recentemente. Homozigose no códon 129 do gene da proteína priônica (PRNP) é fator de risco para doença de Creutzfeldt-Jakob. Este polimorfismo foi estudado como possível fator de risco para doença de Alzheimer (DA). Objetivo Estudar uma possível associação entre o polimorfismo do códon 129 e DA. Métodos Foram investigados 99 pacientes com DA e 111 controles em relação ao polimorfismo do códon 129 e sua associação com desempenho cognitivo. Foram pesquisados outros polimorfismos do PRNP e efeito aditivo do gene da apolipoproteína E (ApoE). Resultados Distribuição no códon 129: 45,5% metionina (MM), 42,2% metionina valina (MV), 12,1% valina (VV) nos pacientes com DA; e 39,6% MM, 50,5% MV, 9,9% VV, nos controles (p >0.05). Não houve diferença no desempenho cognitivo em relação ao códon 129. Estratificação pelo genótipo do ApoE não mostrou diferença entre grupos. Conclusão Polimorfismo do códon 129 não é fator de risco para DA em pacientes brasileiros.

Polimorfismos de nucleotídeos únicos em 15 códons do gene da proteína priônica em um rebanho Suffolk afetado com scrapie no Brasil / Single nucleotide polymorphisms at 15 codons of the prion protein gene from a scrapie-affected herd of Suffolk sheep in Brazil

Scrapie is a transmissible spongiform encephalopathy of sheeps and goats, associated with the deposition of a isoform of the prion protein (PrPsc). This isoform presents an altered conformation that leads to aggregation in the host's central nervous and lymphoreticular systems. Predisposition to the prion agent infection can be influenced by specific genotypes related to mutations in amino acids of the PrPsc gene. The most characterized mutations occur at codons 136, 154 and 171, with genotypes VRQ being the most susceptible and ARR the most resistant. In this study we have analyzed polymorphisms in 15 different codons of the PrPsc gene in sheeps from a Suffolk herd from Brazil affected by an outbreak of classical scrapie. Amplicons from the PrPsc gene, encompassing the most relevant altered codons in the protein, were sequenced in order to determine each animal's genotype. We have found polymorphisms at 3 of the 15 analyzed codons (136, 143 and 171). The most variable codon was 171, where all described alleles were identified. A rare polymorphism was found at the 143 codon in 4 percent of the samples analyzed, which has been described as increasing scrapie resistance in otherwise susceptible animals. No other polymorphisms were detected in the remaining 12 analyzed codons, all of them corresponding to the wild-type prion protein. Regarding the risk degree of developing scrapie, most of the animals (96 percent) had genotypes corresponding to risk groups 1 to 3 (very low to moderate), with only 4 percent in the higher risks group. Our data is discussed in relation to preventive measures involving genotyping and positive selection to control the disease.

Scrapie é uma encefalopatia espongiforme transmissível de ovinos e caprinos, associado a deposição da isoforma da proteína priônica (PrPsc). Essa isoforma apresenta uma alteração conformacional que leva ao acúmulo da proteína no sistema nervoso central e linforeticular do hospedeiro. A predisposição a infecção pelo agente priônico pode ser influenciado por genótipos específicos relacionados a mutações na sequência de aminoácidos do gene PrPsc. As principais mutações caracterizadas ocorrem nos códons 136, 154 e 171, sendo o genótipo VRQ o mais suscetível e o genótipo ARR o mais resistente. Nesse estudo nós analisamos os polimorfismos de 15 códons diferentes da gene PrPsc em ovinos de um rebanho da raça Suffolk no Brasil afetado com scrapie clássico. Os amplicons do gene da PrPsc, que contem os códons mais frequentemente encontrados foram sequenciados para determinar o genótipo de cada animal. Nós encontramos 3 polimorfismos do 15 códons analisados (136, 143 e 171). O códon que mais teve variações foi o códon 171, onde todos os alelos foram identificados. Um polimorfismo raro foi encontrado no códon 143, em 4 por cento das amostras analisadas, o qual tem sido descrito por aumentar a resistência a scrapie em animais suscetíveis. Nenhum outro polimorfismo foi detectado nos 12 códons restantes, todos então, correspondendo à proteína priônica selvagem. De acordo com a grau de risco a desenvolver scrapie, a maioria dos animais (96 por cento) tiveram genótipo correspondentes aos grupos de risco 1 a 3 (muito baixo a moderado), e somente 4 por cento no grupo de risco alto. Nossos dados discutem a relação das medidas de prevenção envolvendo a genotipagem e a seleção positiva para o controle da doença.

Enfermedad de Creutzfeldt-Jakob: hallazgos clínicos, electroencefalográficos, imagenológicos y de patología / Creutzfeldt-Jakob disease: clinical, electroencephalografic, pathologic, and imaging characteristics

La enfermedad de Creutzfeld-Jakob (ECJ) hace parte de un grupo de enfermedades transmisibles que se caracterizan por la presencia de encefalopatía espongiforme, donde también se encuentran el kuru, el síndrome Gerstmann-Straussler- Scheinker, y el insomnio fatal familiar. De ellas, la más común es la ECJ (representando aproximadamente el 85 por ciento de casos de encefalopatías espongiformes), con una incidencia anual estimada en 1-2 casos por millón en la población general y de 5 casos por millón en personas entre 60 y 74 años. A pesar de que fue descrita hace ya más de 50 años, no hay hasta el momento ningún tratamiento efectivo, por lo cual la enfermedad es siempre fatal. El promedio de sobrevida es de apenas 1 año una vez hecho el diagnóstico. Describimos el caso de una paciente femenina de 62 años, quien ingresó a nuestra institución con un cuadro de 1 año de evolución de cambios en el comportamiento rápidamente progresivos, demencia y posteriormente alteraciones motoras. La enfermedad progresó hasta llevar a la postración e incapacidad de la paciente para entablar comunicación con su entorno, lo cual obligó a sus familiares a consultar a nuestro centro para su estudio. Los hallazgos neuropatológicos, clínicos e imagenológicos fueron compatibles con una enfermedad de Creutzfeldt-Jakob esporádica.

Creutzfeldt-Jakob Disease (CJD) belongs to a group of infectious diseases characterized by spongiform encephalitis, which also includes Kuru, Gerstmann-Straussler- Scheinker syndrome, and fatal familial insomnia. Amongst these, the most common is CJD (responsible for aproximately 85 per cent of all cases of spongiform encephalitis) with an anual incidence of 1-2 cases in the general population and 5 cases in people with ages 60-74 years. Even though it was described more than 50 years ago there is still no effective treatment, being invariably fatal. Life expectancy is only 1 year after diagnosis. We describe the case of a 65 year old female patient, who was seen at our institution with a 1 year history of rapid decline of her mental function, initially manifest as behavioral changes followed by dementia and later by motor disfunction. During the last months she was bedridden and unable to communicate, which led her family to seek help in our institution. Clinical, neuropathological and imaging characteristics were compatible with sporadic Creutzfeldt-Jakob disease.